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CHEST
Supplement
Background: Neonates and children differ from adults in physiology, pharmacologic responses to
drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children.
Methods: The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines.
Results: We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible,
we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by
consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic
unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL
or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a
protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving
either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection
(Grade 2C).
Conclusions: The evidence supporting most recommendations for antithrombotic therapy in
neonates and children remains weak. Studies addressing appropriate drug target ranges and
monitoring requirements are urgently required in addition to site- and clinical situation-specific
thrombosis management strategies.
CHEST 2012; 141(2)(Suppl):e737Se801S
Abbreviations: ACCP 5 American College of Chest Physicians; AIS 5 arterial ischemic stroke; ALL 5 acute lymphoblastic
leukemia; APLA 5 antiphospholipid antibody; aPTT 5 activated partial thromboplastin time; ASA 5 acetylsalicyclic
acid; BCPS 5 bilateral cavopulmonary shunt; CC 5 cardiac catheterization; CSVT 5 cerebral sinovenous thrombosis;
CVAD 5 central venous access device; FFP 5 fresh frozen plasma; HIT 5 heparin-induced thrombocytopenia;
ICH 5 intracerebral hemorrhage; INR 5 international normalized ratio; IVC 5 inferior vena cava; IVH 5 intraventricular
hemorrhage; LMWH 5 low-molecular-weight heparin; MBTS 5 modified Blalock-Taussig shunt; NEC 5 necrotizing
enterocolitis; PE 5 pulmonary embolism; PFA 5 platelet function analyzer; PFO 5 patent foramen ovale; PICU 5 pediatric
ICU; PTS 5 postthrombotic syndrome; RCT 5 randomized control trial; RR 5 risk ratio; rUK 5 recombinant urokinase; RVT 5 renal vein thrombosis; TCD 5 transcranial Doppler; TE 5 thromboembolism; TIA 5 transient ischemic
attack; tPA 5 tissue plasminogen activator; TPN 5 total parenteral nutrition; UAC 5 umbilical arterial catheter;
UFH 5 unfractionated heparin; UVC 5 umbilical venous catheter; VAD5 ventricular assist device; VKA 5 vitamin
K antagonist
www.chestpubs.org
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Summary of Recommendations
Note on Shaded Text: Throughout this guideline,
shading is used within the summary of recommendations sections to indicate recommendations that are
newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy:
American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.
1.0. We suggest that where possible, pediatric
hematologists with experience in thromboembolism (TE) manage pediatric patients with TE
(Grade 2C). When this is not possible, we suggest
a combination of a neonatologist/pediatrician
and adult hematologist supported by consultation with an experienced pediatric hematologist
(Grade 2C).
1.1. We suggest that therapeutic unfractionated
heparin (UFH) in children is titrated to achieve
a target range of anti-Xa activity of 0.35 to
0.7 units/mL or an activated partial thromboplastin time (aPTT) range that correlates to this
anti-Xa range or to a protamine titration range
Revision accepted August 31, 2011.
Affiliations: From the Haematology Department (Dr Monagle),
The Royal Childrens Hospital, Department of Paediatrics, The
University of Melbourne, Murdoch Childrens Research Institute,
Melbourne, VIC, Australia; Department of Pediatrics (Dr Chan),
McMaster University, Hamilton, ON, Canada; Department of
Pediatrics (Dr Goldenberg), Section of Hematology/Oncology/
Bone Marrow Transplantation and Mountain States Regional
Hemophilia and Thrombosis Center, University of Colorado,
Aurora, CO; Department of Neurology (Dr Ichord), Childrens
Hospital of Philadelphia, Philadelphia, PA; Department of
Pediatrics (Dr Journeycake), University of Texas Southwestern
Medical Center at Dallas, Dallas, TX; Thrombosis and Hemostasis
Unit (Dr Nowak-Gttl), Institute of Clinical Chemistry, University Hospital Kiel, Kiel, Germany; and Department of Biostatistics
and Epidemiology (Dr Vesely), University of Oklahoma Health
Sciences Center, Oklahoma City, OK.
Funding/Support: The Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines received support from
the National Heart, Lung, and Blood Institute [R13 HL104758]
and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer,
Inc; Canyon Pharmaceuticals; and sanofi-aventis US.
Disclaimer: American College of Chest Physician guidelines are
intended for general information only, are not medical advice, and
do not replace professional medical care and physician advice,
which always should be sought for any medical condition. The
complete disclaimer for this guideline can be accessed at http://
chestjournal.chestpubs.org/content/141/2_suppl/1S.
Correspondence to: Sara K. Vesely, PhD, Department of Biostatistics and Epidemiology, The University of Oklahoma Health
Sciences Center, 801 NE 13th St, CHB 309, Oklahoma City,
OK 73104; e-mail: sara-vesely@ouhsc.edu
2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.11-2308
e738S
dren with femoral artery thrombosis, we recommend surgical intervention compared with UFH
therapy alone when there is a contraindication
to thrombolytic therapy and organ or limb death
is imminent (Grade 1C).
2.11. For neonates and children with peripheral
arterial catheters in situ, we recommend UFH
continuous infusion at 0.5 units/mL at 1 mL/h
compared with normal saline (Grade 1A).
2.12. For neonates and children with a peripheral arterial catheter-related TE, we suggest
immediate removal of the catheter (Grade 2B).
For neonates and children with a symptomatic
peripheral arterial catheter-related TE, we
suggest UFH anticoagulation with or without
thrombolysis or surgical thrombectomy and
microvascular repair with subsequent heparin
therapy (Grade 2C).
2.13. For neonates with umbilical arterial catheters (UACs), we suggest UAC placement in a
high rather than a low position (Grade 2B).
2.14. For neonates with UAC, we suggest prophylaxis with a low-dose UFH infusion via the
UAC (heparin concentration of 0.25-1 unit/mL,
total heparin dose of 25-200 units/kg per day) to
maintain patency (Grade 2A).
2.16. For neonates and children requiring
cardiac catheterization (CC) via an artery, we
recommend administration of IV UFH as thromboprophylaxis over no prophylaxis (Grade 1A) or
aspirin (Grade 1B). For neonates and children
requiring CC via an artery, we recommend the
use of UFH doses of 100 units/kg as a bolus compared with a 50-unit/kg bolus (Grade 1B). In prolonged procedures, we suggest further doses of
UFH rather than no further therapy (Grade 2B).
2.17. For neonates with cerebral sinovenous
thrombosis (CSVT) without significant intracranial hemorrhage, we suggest anticoagulation, initially with UFH or LMWH and subsequently with
LMWH, for a total therapy duration between
6 weeks and 3 months rather than shorter or
longer treatment duration (Grade 2C). For neonates with CSVT with significant hemorrhage,
we suggest either (1) anticoagulation or (2) supportive care with radiologic monitoring of the
thrombosis at 5 to 7 days and anticoagulation if
thrombus extension is noted as compared with
no therapy (Grade 2C).
2.18. For neonates with a first arterial ischemic
stroke (AIS), in the absence of a documented,
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2.19. For neonates with a first AIS and a documented cardioembolic source, we suggest anticoagulation with UFH or LMWH (Grade 2C).
2.20. For neonates with recurrent AIS, we suggest anticoagulant or aspirin therapy (Grade 2C).
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(Grade 2C). For children with CSVT with significant hemorrhage, we suggest initial anticoagulation as for children without hemorrhage or
radiologic monitoring of the thrombosis at 5 to
7 days and anticoagulation if thrombus extension is noted at that time (Grade 2C). In children
with CSVT and potentially recurrent risk factors
(for example, nephrotic syndrome, asparaginase
therapy), we suggest prophylactic anticoagulation at times of risk factor recurrence (Grade 2C).
We suggest thrombolysis, thrombectomy, or
surgical decompression only in children with
severe CSVT in whom there is no improvement
with initial UFH therapy (Grade 2C).
2.52. For children with acute AIS, with or without thrombophilia, we recommend UFH or
LMWH or aspirin as initial therapy until dissection and embolic causes have been excluded
(Grade 1C). For children with acute AIS, we
suggest, once dissection and cardioembolic
causes are excluded, daily aspirin prophylaxis
for a minimum of 2 years as compared with
no antithrombotic therapy (Grade 2C). For children receiving aspirin who have recurrent AIS
or transient ischemic attacks (TIAs), we suggest changing to clopidogrel or anticoagulant
therapy with LMWH or VKA (Grade 2C). For
children with AIS, we recommend against the
use of thrombolysis (tPA) or mechanical thrombectomy outside of specific research protocols
(Grade 1C).
2.53. For AIS secondary to cardioembolic causes,
we suggest anticoagulant therapy with LMWH
or VKAs for at least 3 months (Grade 2C). For
AIS secondary to cardioembolic causes in children with demonstrated right-to-left shunts (eg,
patent foramen ovale [PFO]), we suggest surgical closure of the shunt (Grade 2C).
2.54. For AIS secondary to dissection, we suggest anticoagulant therapy with LMWH or VKAs
for at least 6 weeks (Grade 2C). Ongoing treatment will depend on radiologic assessment of
degree and extent of stenosis and evidence of
recurrent ischemic events.
2.51. For children with CSVT without significant intracranial hemorrhage, we recommend
anticoagulation initially with UFH or LMWH
and subsequently with LMWH or VKA for a
minimum of 3 months relative to no anticoagulation (Grade 1B). In children who after 3 months
of therapy still experience occlusion of CSVT
or ongoing symptoms, we suggest administration of a further 3 months of anticoagulation
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perspective of treatment guidelines remains controversial. Young adults (18-25 years) are sparsely represented in most adult data about management of TE.
In other areas of medicine, this demographic is being
recognized as a separate entity, which requires specific study.9 In addition to chronologic age, clinicians
need to consider factors such as physical development, stage of puberty, and emotional and intellectual development. Adolescents are transitioned to
adult services after they leave school or between
16 and 21 years of age, depending on their local jurisdiction. In addition, there is considerable variation
based on individual circumstances.
Comprehensive literature searches were performed
as per the American College of Chest Physicians
(ACCP) guidelines based on the questions presented
in Table 1, and recommendations are based on the
ACCP grades of recommendation.10 Where possible,
because of the physiologic and pathophysiologic differences as well as the markedly different implications of therapy, recommendations are presented for
neonates and children separately. However, in cases
where the available data do not adequately differentiate between the two age groups, the combined recommendations are presented.
1.0 Antithrombotic Therapy
in Pediatric Patients
The use of antithrombotic drugs in pediatric patients
differs from adults.11 First, the epidemiology of TE in
pediatric patients differs from that seen in adults.12-24
Second, the hemostatic system is a dynamic, evolving
entity that likely affects not only the frequency and
natural history of TEs in children but also the response
to therapeutic agents.4,25,26 Third, the distribution,
binding, and clearance of antithrombotic drugs are
age dependent.27-29 Fourth, the frequency and type
of intercurrent illnesses and concurrent medications
vary with age. Fifth, the need for general anesthesia to
perform many diagnostic studies in pediatric patients
has an impact on the ability to investigate and monitor TEs and, hence, the confidence one can have in
therapeutic decisions. Sixth, limited vascular access
reduces the ability to effectively deliver some antithrombotic therapies and can influence the choice of
antithrombotic agent. Often, the only vascular access
available is used for drug delivery, so accurate monitoring of blood anticoagulant levels is difficult. Seventh, specific pediatric formulations of antithrombotic
drugs are not available, making accurate, reproducible dosing difficult, which is especially the case
for vitamin K antagonists (VKAs) (no suspension/liquid preparation) and low-molecular-weight heparin
(LMWH) (in many countries, the most readily available
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Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age) and
children
Neonates (premature
and term up to 28 d
corrected age) and
children
2.1
2.2-2.3
2.2-2.3
2.4-2.5
2.4-2.5
2.6
2.7
Section
Treatment
Prophylaxis
Prophylaxis
Prophylaxis
Treatment
Treatment
Treatment
Informal Question
Blalock-Taussig
shunt-blocked
Blalock-Taussig shunt
CVAD
CVAD
Population
Thrombolysis
Anticoagulation (heparin or
LMWH), aspirin,
clopidogrel
Anticoagulation,
thrombolysis
Anticoagulation
Anticoagulation,
thrombolysis
Intervention (s)
Surgical intervention
No therapy
Comparator
PICO Question
Outcome
Mortality
Pulmonary embolus
Paradoxical stroke
Postthrombotic syndrome
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Mortality
Renal failure
Renal atrophy
Hypertension
Extension
Recurrent VTE
Hemorrhage (major and CNS)
Mortality
Renal failure
Renal atrophy
Hypertension
Extension
Recurrent VTE
Hemorrhage (major and CNS)
Patency
Sepsis/CVAD infection
DVT
PE
Hemorrhage (major and CNS)
Patency
Sepsis/CVAD infection
DVT
PE
Hemorrhage (major and CNS
Intracardiac thrombosis
(includes shunt thrombosis)
Mortality
Tissue loss
Hemorrhage (major and CNS)
Intracardiac thrombosis
(includes shunt thrombosis)
Mortality
Tissue loss
Hemorrhage (major and CNS)
Table 1[Introduction] PICO Questions for Antithrombotic Therapy in Neonates and Children
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
Methodology
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e745S
Neonates (premature
and term up to 28 d
corrected age) and
children
Neonates (premature
and term up to 28 d
corrected age) and
children
Neonates (premature
and term up to 28 d
corrected age) and
children
Neonates (premature
and term up to 28 d
corrected age) and
children
Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age)
2.9-2.10
Neonates (premature
and term up to 28 d
corrected age)
Neonates (premature
and term up to 28 d
corrected age) and
children
2.15
2.16
2.13-2.14
2.13-2.14
2.12
2.11
2.9-2.10
Neonates (premature
and term up to 28 d
corrected age)
2.8
Section
Prophylaxis
Treatment
Prophylaxis
Prophylaxis
Treatment
Prophylaxis
Treatment
Treatment
Prophylaxis
Informal Question
Population
Cardiac catheter
Aortic thrombosis
(UAC related or
spontaneous)
UAC
UAC
Peripheral arterial
thrombosis (excluding
femoral artery)
Peripheral arterial
catheters (excluding
femoral artery)
Femoral artery
thrombosis
Femoral artery
thrombosis
Stage 1 Norwood
Intervention (s)
Heparin prophylaxis,
Aspirin prophylaxis
Thrombolysis
Heparin prophylaxis
Exposure (high
position [. T10])
Thrombolysis
Thrombolysis (followed by
standard anticoagulation
or antiplatelet therapy),
thrombectomy
Thrombolysis
Anticoagulation
Anticoagulation
Outcome
No therapy
Anticoagulation
No therapy
No therapy,
thrombectomy,
anticoagulation,
antiplatelet therapy
Low position (L3-L5)
Aortic thrombosis
NEC
Hemorrhage (major and CNS)
Patency
Aortic thrombosis
Hemorrhage (major and CNS)
NEC
Embolization (eg, digital artery)
Tissue loss
Mortality
Mortality
Tissue loss
Renal impairment
Hypertension
NEC
Embolization
Hemorrhage (major and CNS)
Femoral artery thrombosis
Embolization non-CNS
Cardioembolic stroke
Hemorrhage (major and CNS)
Tissue loss
Growth failure
Hemorrhage (major and CNS)
Intracardiac thrombosis
Mortality
Tissue loss
Hemorrhage (major and CNS)
No therapy or
Claudication
antiplatelet therapy
Leg shortening
Tissue loss
Hemorrhage (major and CNS)
Anticoagulation or
Claudication
antiplatelet therapy
Leg shortening
(without thrombolysis), Tissue loss
each other
Hemorrhage (major and CNS)
No therapy
Tissue loss
Growth failure
Hemorrhage (major and CNS)
Antiplatelet therapy
Comparator
PICO Question
Table 1Continued
Methodology
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
e746S
Neonates (premature
and term up to 28 d
corrected age)
2.21
Children (day 28 to
16-18 y)
Neonates (premature
and term up to 28 d
corrected age)
2.18-2.20
2.23
Neonates (premature
and term up to 28 d
corrected age)
2.18-2.20
Children (day 28 to
16-18 y)
Neonates (premature
and term up to 28 d
corrected age)
2.18-2.20
2.22
Neonates (premature
and term up to 28 d
corrected age)
2.17
Section
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Treatment
Informal Question
Population
Purpura fulminans
AIS (recurrent)
CSVT
Intervention (s)
Comparator
Anticoagulation
No therapy
Antiplatelet therapy
or no therapy
No therapy
No therapy
Systemic thrombolysis
Anticoagulation
(in conjunction with
anticoagulant therapy),
local thrombolysis
pharmacomechanical
thrombolysis (in conjunction
with anticoagulant therapy)
Anticoagulation
Protein C replacement,
fresh frozen plasma
Antiplatelet therapy or
anticoagulation
Anticoagulation
Anticoagulation
Anticoagulation
PICO Question
Table 1Continued
Outcome
Methodology
Mortality
Functional status
Hemorrhage (major and CNS)
Recurrent AIS (rare)
Mortality
Functional status
Hemorrhage (major and CNS)
Recurrent AIS (rare)
Mortality
Vision
Neurologic outcome
Primary thrombosis
Recurrent thrombosis (among
those with major vessel
thrombosis at presentation)
Mortality
Primary PE
Paradoxical stroke
Postthrombotic syndrome
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Mortality
Primary PE
Paradoxical stroke
Postthrombotic syndrome
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Phlegmasia cerulea dolens
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
Mortality
RCT, observational
Functional status
studies
Extension
Recurrent CSVT
Hemorrhage (major and CNS)
Visual outcomes/need for surgical
management of increased ICP
(fenestration shunt)
Mortality
RCT, observational
Functional status
studies
Hemorrhage (major and CNS)
Recurrent AIS (rare)
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e747S
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y) with
cancer or
leukemia
Children (day 28 to
16-18 y) with
antiphospholipid
antibodies or lupus
anticoagulant
Children (day 28
to 16-18 yr)
with positive
thrombophilia
Children (day 28 to
16-18 y) with
structural venous
abnormality
Children (day 28 to
16-18 y)
2.24
2.25
2.26
2.27
2.28
2.29
Section
Treatment
Treatment
Treatment
duration/
intensity
Treatment
duration/
intensity
Treatment
duration/
intensity
Treatment
Informal Question
Population
Thrombolysis, surgical
thrombectomy
(followed by standard
anticoagulation or
antiplatelet therapy)
Interventional radiology
or surgical stenting,
dilatation or bypass
Anticoagulation,
Interventional radiology
or surgical stenting,
dilatation or bypass
Anticoagulation
(heparin/LMWH)
Anticoagulation
(heparin/LMWH)
Intervention (s)
Anticoagulation
(without thrombolysis
or surgical
thrombectomy),
each other
Anticoagulation
VKAs
VKAs
Anticoagulation
Comparator
PICO Question
Table 1Continued
Mortality
Primary PE
Paradoxical stroke
Postthrombotic syndrome
Filter migration or filter fracture
Filter nonretrievability (for
temporary filters)
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Mortality
Primary PE
Paradoxical stroke
Postthrombotic syndrome
Hemorrhage (major and CNS)
Recurrence (DVT or PE)
Mortality
Primary PE
Paradoxical stroke
Postthrombotic syndrome
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Mortality
Primary Pulmonary embolus
Paradoxical stroke
Postthrombotic syndrome
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Mortality
Extension
Primary PE
Paradoxical stroke
Postthrombotic syndrome
Recurrence (DVT or PE)
Hemorrhage (major and CNS)
Mortality
PE
Paradoxical stroke
Postthrombotic syndrome
Recurrent VTE
Hemorrhage (major and CNS)
Outcome
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
Methodology
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Children (day 28 to
16-18 y)
Children (day 28
to 16-18 y)
with positive
thrombophilia
2.30-2.34
2.35
Children (day 28 to
16-18 y)
2.30-2.34
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.30-2.34
2.30-2.34
Prophylaxis
2.30-2.34
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Informal Question
Children (day 28 to
16-18 y)
Section
Population
CVAD
Intervention (s)
Anticoagulation prophylaxis
Systemic anticoagulation
prophylaxis
Systemic anticoagulation
prophylaxis
Systemic anticoagulation
prophylaxis
Systemic anticoagulation
prophylaxis
Local heparin
(1-2 units/mL infusion),
heparin lock,
intermittent local
thrombolysis
No therapy
No therapy
No therapy
No therapy
No therapy
No therapy
Comparator
PICO Question
Table 1Continued
Outcome
Patency
CVAD dysfunction
Sepsis/CVAD infection
DVT
PE
Hemorrhage (major and CNS)
Patency
CVAD dysfunction
Sepsis/CVAD infection
DVT
PE
Hemorrhage (major and CNS)
mortality
Patency
CVAD dysfunction
Sepsis/CVAD infection
DVT
PE
Major bleeding
Mortality
Patency
CVAD dysfunction
Sepsis/CVAD infection
DVT
PE
Hemorrhage (major and CNS)
Mortality
Postthrombotic syndrome
Patency
CVAD dysfunction
Sepsis/CVAD infection
DVT
PE
Hemorrhage (major and CNS)
Mortality
Postthrombotic syndrome
Intracardiac thrombosis
Mortality
Tissue loss
Hemorrhage (major and CNS)
Ischemic stroke
Fontan surgery
Methodology
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
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e749S
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.36
2.37
2.38
2.39
2.40-2.42
2.40-2.42
2.40-2.42
2.43
2.44
Section
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Prophylaxis
Informal Question
Population
Ventricular assist
devices
Mechanical prosthetic
heart valves with a
history of thrombotic
events while on
antithrombotic therapy
Bacterial endocarditis
Mechanical prosthetic
heart valves
Biologic prosthetic
heart valves
Primary pulmonary
hypertension
Dilated cardiomyopathy
Endovascular stents
Fontan surgery
Intervention (s)
Anticoagulation,
antiplatelet agents,
prophylaxis
Anticoagulation
Combination,
antiplatelet agents,
and VKAs
Antiplatelet agents,
anticoagulation,
antiplatelet agents,
and VKAs
VKAs or aspirin
VKAs
VKAs or aspirin
prophylaxis
Heparin or LMWH or
aspirin prophylaxis
Anticoagulation,
antiplatelet therapy
No therapy
No therapy
VKAs alone
No therapy
No therapy
No therapy
No therapy
No therapy
No therapy
Comparator
PICO Question
Table 1Continued
Outcome
Intracardiac thrombosis
Mortality
Fontan takedown
Ischemic stroke
Hemorrhage (major and CNS)
Patency
Mortality
Pulmonary emboli
Ischemic stroke
Mortality
Thrombosis
Ischemic stroke
Hemorrhage (major and CNS)
Mortality
Thrombosis
Heart/lung transplantation
Hemorrhage (major and CNS)
Mortality
Valve replacement
Thrombosis
Ischemic stroke
Hemorrhage (major and CNS)
Mortality
Valve replacement
Thrombosis
Ischemic stroke
Hemorrhage (major and CNS)
Mortality
Valve replacement
Thrombosis
Ischemic stroke
Hemorrhage (major and CNS)
Primary embolic stroke
Mortality
Hemorrhage (major and CNS)
Mortality
Thrombosis
Ischemic stroke
Blocked circuit requiring surgery
Hemorrhage (major and CNS)
Methodology
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
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Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.48-2.50
2.53
Children (day 28 to
16-18 y)
2.48-2.50
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.48-2.50
2.52
Children (day 28
to 16-18 y)
2.47
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.45-2.46
2.51
Prophylaxis
2.45-2.46
Population
Treatment
Treatment
AIS (undetermined
cause, in situ
thrombosis,
thrombophilia)
AIS (cardioembolic)
Treatment
Treatment
Kawasaki disease
Hemodialysis
(arteriovenous
fistula or CVAD)
Hemodialysis (CVAD)
Hemodialysis
(arteriovenous fistula)
Treatment
Prophylaxis
Prophylaxis
(during
procedure)
Prophylaxis
Informal Question
Children (day 28 to
16-18 y)
Section
Intervention (s)
Anticoagulation
Anticoagulaton,
thrombolysis (followed
by standard
anticoagulation)
Anticoagulation or aspirin,
thrombolysis
Thrombolysis
Anticoagulation
Anticoagulation
Continuous
anticoagulation,
procedural UFH
or LMWH
Continuous
anticoagulation,
procedural UFH
or LMWH
Aspirin
Anticoagulation
Antiplatelet therapy
No therapy
No therapy
No therapy
No therapy
Comparator
PICO Question
Table 1Continued
Outcome
Mortality
Thrombus extension
Functional status
Hemorrhage (major and CNS)
Mortality
Recurrent AIS
Functional status
Hemorrhage (major and CNS)
Mortality
Recurrent AIS
Functional status
Hemorrhage (major and CNS)
Mortality
Thrombosis
Shunt dysfunction
Shunt infection
Hemorrhage (major and CNS)
Mortality
Thrombosis
CVAD dysfunction
Sepsis/CVAD infection
Hemorrhage (major and CNS)
Thrombosis
CVAD dysfunction
Sepsis/CVAD infection
Dialysis failure
Hemorrhage (major and CNS)
Coronary aneurysms
Myocardial infarction
Mortality
Hemorrhage (major and CNS)
Myocardial infarction
Mortality
Hemorrhage (major and CNS)
Myocardial infarction
Mortality
Hemorrhage (major and CNS)
Methodology
(Continued)
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
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Prophylaxis
Treatment
Treatment
Treatment
Treatment
Treatment
Informal Question
Population
AIS (moyamoya,
non-sickle cell)
AIS (moyamoya,
non-sickle cell)
AIS (vasculopathy
other than dissection
or moyamoya)
AIS (dissection)
Intervention (s)
Chronic transfusion
program
Exchange transfusion
Surgical revascularization
(direct/indirect)
Aspirin (with/without
neurosurgical direct/
indirect revascularization),
surgical revascularization
(direct/indirect)
Anticoagulation or aspirin
Anticoagulation
Comparator
No treatment
No antithrombotic
therapy (with/without
neurosurgical direct/
indirect surgical
revascularization),
each other
Antiplatelet therapy
(without direct/
indirect surgical
revascularization)
No treatment
No therapy
Aspirin
Outcome
Mortality
Recurrent AIS
Functional status
Hemorrhage (major and CNS)
Mortality
Recurrent AIS
Functional status
Intracranial hemorrhage
Mortality
Recurrent AIS
Functional status
Intracranial hemorrhage
Mortality
Recurrent AIS
Functional status
Intracranial hemorrhage
Mortality
Recurrent AIS
Functional status
Hemorrhage (major and CNS)
Mortality
Recurrent AIS
Functional status
Hemorrhage (major and CNS)
Methodology
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
RCT, observational
studies
AIS 5 arterial ischemic stroke; CSVT 5 cerebral sinovenous thrombosis; CVAD 5 central venous assist device; CVL 5 central venous line; IVC 5 inferior vena cava; LMWH 5 low-molecular-weight heparin;
NEC 5 necrotizing enterocolitis; PE 5 pulmonary embolus(ism); PICO 5 populations, interventions, comparators, outcomes; PICU 5 pediatric ICU; RCT 5 randomized controlled trial; TPN 5 total
parenteral nutrition; UAC 5 umbilical arterial catheter; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist.
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.56-2.57
2.58-2.59
Children (day 28 to
16-18 y)
2.56-2.57
Children (day 28 to
16-18 y)
Children (day 28 to
16-18 y)
2.55
2.58-2.59
Children (day 28 to
16-18 y)
2.54
Section
PICO Question
Table 1Continued
Table 2[Section 1.1.1] Factors in Children That Affect the Action of UFH
UFH Factor
Age-Related Difference
Evidence
Strong: multiple studies Andrew et al (1990),32
Andrew (1992),33 Andrew et al (1992),34
Monagle et al (2006)26
Strong: multiple studies Ignjatovic et al (2007),35
Andrew et al (1990),32 Andrew (1994)12
Moderate: Newall et al (2010),5 Newall et al
(2009),36 Ignjatovic et al (2006)37
Moderate: Ignjatovic et al (2010),29 Newall et al
(2008),28 Ignjatovic et al (2006),27
Ignjatovic et al (2006)37
Moderate: Ignjatovic et al (2006)37
TFPI 5 tissue factor pathway inhibitor. See Table 1 legend for expansion of other abbreviation.
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Table 3[Section 1.1.5] Protocol for Systemic Heparin Administration and Adjustment for Pediatric Patients
I. Loading dose: heparin 75 units/kg IV over 10 min
II. Initial maintenance dose: 28 units/kg per h for infants aged , 1 y; 20 units/kg per h for children aged . 1 y
III. Adjust heparin to maintain aPTT of 60-85 s (assuming this reflects an anti-Xa level of 0.35-0.70):
aPTT, s
Bolus, units/kg
Hold, min
% Rate Change
50
0
, 50
1 10
50-59
0
0
1 10
60-85
0
0
0
86-95
0
0
210
96-120
0
30
210
0
60
. 120
215
IV. Obtain blood for aPTT 4 h after administration of the heparin loading dose and 4 h after every change in the infusion rate
V. When aPTT values are therapeutic, a daily CBC and aPTT
Repeat aPTT
4h
4h
Next day
4h
4h
4h
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patients had additional risk factors before this complication. These limited data, in conjunction with adult
data, would support avoidance of long-term use of
UFH in children when alternative anticoagulants
are available. This recommendation is strengthened
by the physiologic changes in bone seen in childhood,
which potentially places children at increased risk of
osteoporosis compared with adults.63,64
As in adults, the diagnosis of heparin-induced
thrombocytopenia (HIT) in children remains problematic.65 Studies examining the frequency of HIT in
children have varied in their reported results, likely
because of differences in patient inclusion and laboratory techniques.30,66-70 Rates vary from almost zero in
unselected heparinized children30 to 2.3% in children
in the PICU.68 UFH exposure in these cases ranged
from low-dose exposure during heparin flushes used
in maintaining patency of venous access devices
(VADs), to supratherapeutic doses given during cardiopulmonary bypass and hemodialysis. Presumed HIT
currently is the most common indication for children
to receive novel anticoagulant drugs, and the outcome
for these children often is poor because of complications of the novel anticoagulants.71 Danaparoid,
hirudin, and argatroban are alternatives to UFH in
children with HIT.65,72-99
1.1.7 Treatment of Heparin-Induced Bleeding: If
UFH needs to be discontinued for clinical reasons,
termination of the infusion usually will suffice because
of the rapid clearance of UFH. If immediate reversal
is required, protamine sulfate rapidly neutralizes
UFH activity. The required dose of protamine sulfate
is based on the amount of UFH received in the previous 2 h (Table 4).
Recommendation
1.1. We suggest that therapeutic UFH in children
is titrated to achieve a target range of anti-Xa
activity of 0.35 to 0.7 units/mL or an aPTT range
that correlates to this anti-Xa range or to a
protamine titration range of 0.2 to 0.4 units/mL
Table 4[Section 1.1.7] Reversal of Heparin Therapy
Time Since Last
Heparin Dose, min
, 30
30-60
60-120
. 120
Protamine Dose
1.0 mg/100 units heparin received
0.5-0.75 mg/100 units heparin received
0.375-0.5 mg/100 units heparin received
0.25-0.375 mg/100 units heparin received
Weight
Age
Weight-dependent dose
of reviparin
, 5 kg
na
Age-dependent dose
of enoxaparina
50 u/kg/dose q12h
. 5 kg
na
30 u/kg/dose q12h
na
, 2 mo
92 52 u/kg/dose q24h
na
. 2 mo
na
all
Age-dependent dose
of tinzaparin
na
0-2 mo
275 u/kg
na
na
na
na
2-12 mo
1-5 y
5-10 y
10-16 y
250 u/kg
240 u/kg
200 u/kg
175 u/kg
na 5 not applicable.
a Enoxaparin has 110 anti-factor Xa units/mg.115
b Dalteparin has 100 anti-factor Xa units/mg.
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Recommendation
1.2. We suggest, for neonates and children
receiving either once- or twice-daily therapeutic
LMWH, that the drug be monitored to a target
anti-Xa activity range of 0.5 to 1.0 units/mL in a
sample taken 4 to 6 h after subcutaneous injection or 0.5 to 0.8 units/mL in a sample taken 2 to
6 h after subcutaneous injection (Grade 2C).
1.3 VKAs in Neonates and Children
VKAs are problematic in newborns for several
reasons. First, the plasma levels of the vitamin Kdependent coagulation factors are physiologically
decreased in newborns to levels that are comparable to those achieved in adults receiving therapeutic
amounts of VKAs with target international normalized ratios (INRs) of 2.0 to 3.0. Second, infant formula
is supplemented with vitamin K to prevent hemorrhagic disease of the newborn. In contrast, breast
milk has low concentrations of vitamin K, making
breast-fed infants very sensitive to VKAs.131,132 The
latter can be compensated for by feeding breast-fed
neonates 30 to 60 mL of formula each day. Third,
VKAs are only available in tablet form in most countries. Although the tablets can be dissolved in water
for administration to newborns, neither stability data
nor critical assessment of this practice are available.
Fourth, VKAs require frequent monitoring in newborns
because of the rapidly changing physiologic values of
the vitamin K-dependent coagulation proteins and
frequent changes in medications and diet.133 Finally,
although there is substantial information on the use
of VKAs in children aged . 3 months, there is little
efficacy or safety information specific to their use
in neonates. Problems of vascular access, frequent
intercurrent infections, concurrent medications, lack
of liquid preparation, and poor compliance continue
to make VKAs difficult to manage in older children as
well.133
Warfarin is the most commonly used VKA in children.134-138 Acenocoumarol is used in some European
and South American countries.139,140 Phenprocoumon
is the preferred VKA in some parts of Europe. No
data about doses of these other agents have been
reported. At present, the choice of VKA often is influenced by previous experience and familiarity within
a country or region. The remainder of this section
will refer to warfarin unless stated otherwise.
The current therapeutic INR ranges for children
are directly extrapolated from recommendations for
adult patients because there are no clinical trials that
have assessed the optimal INR range for children.
Thus, for most indications, the therapeutic target INR
is 2.5 (range, 2.0-3.0), and the low-dose prophylactic
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III
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1.7 Clopidogrel
1.8.1 Background: At birth, plasma concentrations of plasminogen are 50% of adult values
(21 mg/100 mL).212-214 The decreased levels of plasminogen in newborns slows the generation of plasmin215
and reduces the thrombolytic effects of streptokinase,
urokinase and tissue plasminogen activator (tPA)
in an in vitro fibrin clot system.34 A similar response
occurs in children with acquired plasminogen deficiency. Supplementation with plasminogen increases
the thrombolytic effect of all three agents34,216
In pediatric patients, tPA is the agent of
choice.34,216-220 Reasons for this preference include a
previous US Food and Drug Administration warning regarding urokinase, experimental evidence of
improved clot lysis in vitro compared with urokinase
and streptokinase, fibrin specificity, and low immunogenicity.221,222 However, tPA is considerably more
expensive than either streptokinase or urokinase, and
the increased in vitro clot lysis by tPA has not been
demonstrated in clinical trials in children. There is
minimal experience with other thrombolytic agents
in children.217,219,223 A survey showed no consensus in
indications for thrombolysis, dose, mode of delivery,
or duration of therapy.220
Success rates for thrombolysis in pediatric patients
vary. Albisetti217 described complete resolution in
64% of 413 children receiving streptokinase, urokinase, or tPA (53%, 43%, and 69%, respectively).
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21 (14%) died after discharge.292 Autopsies in 15 children attributed death to shunt thrombosis in five
infants (33%) and to myocardial infarction in two
(13%). The mortality of patients discharged on aspirin (11%) was almost identical to that of patients
discharged on no antithrombotic therapy (12.3%).292
Wells et al291 described the histologic appearance
of 155 MBTSs electively taken down at a mean of
8 months of age and reported that 21% had . 50%
stenosis; however, the role of thrombosis vs myofibroblastic proliferation in causing the obstruction was unclear.
A retrospective series of 546 MBTS procedures
reported no significant differences between heparin
and no heparin in early failure rate (1.4% vs 3.4%,
P 5 .29), in later failure rate (9.1% vs 13.6%, P 5 .17),
or between aspirin and no aspirin (11.0% vs 6.7%,
P 5 .18),293 and Li et al294 reported reduced thrombosis in a large cohort of patients treated with aspirin
for 12 months after shunt surgery. In another, much
smaller case study, aspirin was reported to decrease
the incidence of stent thrombosis after MBTS surgery.295 Mullen et al296 reported the safety of MBTS
without postoperative heparin therapy. No data support the use of ongoing anticoagulant therapy (heparin, LMWH, or VKAs) after MBTS surgery. No
published RCTs guide the antithrombotic medical
management of patients with MBTSs.
Recommendation
2.6. For neonates and children having MBTS, we
suggest intraoperative UFH therapy (Grade 2C).
For neonates and children after MBTS surgery,
we suggest either aspirin or no antithrombotic
therapy as compared with prolonged LMWH
or VKAs (Grade 2C).
2.7 Therapy for Blocked Blalock-Taussig
Shunts and MBTSs
Options for acute management of a thrombosed
MBTSs include reoperation with shunt takedown
and replacement, balloon angioplasty with or without
percutaneous catheter thrombectomy, or thrombolysis.297-299 There are insufficient data to recommend
any one specific therapy over another.
2.8 Thromboprophylaxis for Stage 1 Norwood
Procedures
Given that the standard Norwood procedure
involves an MBTS and that the shunt size often is
small (3.0 or 3.5 mm), prophylactic antithrombotic
recommendations following Norwood procedure are
based on those for MBTSs.300,301 Whether a different
strategy is required for Sano modifications of Norwood procedure is unknown.302
Antithrombotic Therapy in Neonates and Children
Recommendations
2.9. For neonates and children with acute femoral
artery thrombosis, we recommend therapeutic
doses of IV UFH as initial therapy compared
with aspirin or no therapy (Grade 1B) or LMWH
(Grade 2C). We suggest subsequent conversion
to LMWH, or else continuation of UFH, to complete 5 to 7 days of therapeutic anticoagulation
as compared with a shorter or longer duration
(Grade 2C).
2.10. For neonates and children with limbthreatening or organ-threatening (via proximal
extension) femoral artery thrombosis who fail
to respond to initial UFH therapy and who have
no known contraindications, we recommend
thrombolysis (Grade 1C). For neonates and children with femoral artery thrombosis, we recommend surgical intervention compared with UFH
therapy alone when there is a contraindication to
thrombolytic therapy and organ or limb death is
imminent (Grade 1C).
www.chestpubs.org
Recommendation
2.11. For neonates and children with peripheral
arterial catheters in situ, we recommend UFH
continuous infusion at 0.5 units/mL at 1 mL/h
compared with normal saline (Grade 1A).
2.12 Therapy for Peripheral Artery
Thrombosis Secondary to Peripheral Artery
Catheters in Neonates and Children
Peripheral artery thrombosis in neonates and children is almost always due to arterial puncture or catheters.327 Tarry et al328 identified 44 cases of peripheral
arterial TEs secondary to catheterizations or arterial
punctures in children with nephrotic syndrome.
Friedman et al309 reported the use of microvascular
surgery in a heterogeneous group of neonates with
vascular injury. Albisetti et al329 reported 54 arterial
thromboses in 51 children of whom 96% had peripheral artery thrombosis. One case series of predominantly neonates proposed an algorithm to assist in
determining the role of surgery vs thrombolysis and
anticoagulation.263
Recommendation
2.12. For neonates and children with a peripheral arterial catheter-related TE, we suggest
immediate removal of the catheter (Grade 2B).
For neonates and children with a symptomatic
peripheral arterial catheter-related TE, we
suggest UFH anticoagulation with or without
thrombolysis or surgical thrombectomy and microvascular repair with subsequent heparin therapy (Grade 2C).
2.13-2.14 Prophylaxis of Umbilical Arterial
Catheters in Neonates
The incidence of symptomatic thrombosis of umbilical arterial catheters (UACs) is 1% to 3%,330-332 with
studies using sequential imaging and autopsy data
reporting a higher incidence.333,334 Factors increasing
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1. n 5 296 catheters
2. n 5 42 catheters
Children
RCT
Rais-Bahrami et al324/1990
Newborns
1. n 5 30
2. n 5 30
Mean hours:
1. 78.1 h
2. 44.8 h
NS
Catheter failure:
1. 22%
2. 7%
P 5 .02
Mean hours for infants requiring
premature removal of catheters:
1. n 5 16, 107 h
2. n 5 21, 39 h
P , .001
Nonelective removal:
2 vs 1, NS
3 vs 1, P, .002
Time until catheter failure was
longer in patients receiving
papaverine (log-rank, P 5 .02)
1. n 5 124
2. n 5 115
1 unit/mL heparin:
1. placebo
2. papaverine (60 mg/500 mL)
Ages 3 wk to 18 y
RCT
Heulitt et al /1993
Comments
Duration of Catheter Patency
No. Patients
Groups
Age
Design
Study
326
Table 7[Recommendation 2.11] Prophylaxis for Peripheral Arterial Catheters in Neonates and Children
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risk include longer catheter duration333 and the positioning of the UAC tip, which are routinely described
as high or low. The high position is at the level of the
T6 to T9 thoracic vertebral bodies. In this position,
the catheter tip is placed above the celiac axis,
superior mesenteric artery, and renal arteries and is,
therefore, above the diaphragm. The low position is
at the level of the L3 to L4 lumbar vertebral bodies,
and the position is therefore below these major vessels but above the aortic bifurcation. Barrington285
conducted a systematic review of five RCTs and
one alternate-assignment trial comparing outcomes
of clinical ischemic events, aortic thrombosis, IVH,
mortality, NEC, hypertension, and hematuria. Clinical ischemic events (RR, 0.53; 95% CI, 0.44-0.63;
consistent across five studies included) and aortic
thrombosis (RR, 0.31; 95% CI, 0.11-0.86; one study
with 62 infants) were less likely with high vs low
UAC placement; other outcomes were not significantly different between high and low placement.285
The short-term consequences of UAC-related thrombosis depend on the extent of the thrombosis but
include lower-limb ischemia,330,332,335 congestive cardiac failure, impaired renal function, and hypertension.336 Embolic events are also reported, and UAC
thrombosis has been linked to the development of
NEC.337,338 Longer-term outcomes include death,339
persistent renovascular hypertension, and lower-limb
growth abnormalities.340
Six RCTs addressed the use of low-dose heparin
infusions in neonates with UACs,341-346 which was the
subject of a systematic review by Barrington.347 Five
studies compared the use of UFH in the UAC infusate
with or without additional UFH in flush solutions
vs no UFH, whereas one compared the use of UFH
in the infusate vs UFH in the flush solution. End
points assessed in these studies included catheter
patency, aortic occlusion, other ischemic events, coagulation abnormalities, IVH, and hypertension. Two
studies used objective imaging to assess the incidence
of thrombosis.344,345 A reduced incidence of catheter
occlusion was consistent in the studies (four used UFH
1 unit/mL, and one used UFH 0.25 units/mL341), with
a pooled relative risk of 0.19 (95% CI, 0.10-0.33).
Despite the consistent reduction in catheter occlusion, none of these studies were able to demonstrate
that UFH had any effect on aortic thrombosis or
other ischemic events. There was also no significant
difference in the incidence of IVH.
McDonald et al348 reported the use of full systemic
UFH vs low-dose UFH in an RCT that included only
19 infants. Although there was a trend toward a
reduced incidence of aortic thrombosis, this did not
achieve statistical significance, and data on the incidence of IVH and other coagulation abnormalities
were not reported.
Antithrombotic Therapy in Neonates and Children
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Recommendation
2.17. For neonates with CSVT without significant ICH, we suggest anticoagulation, initially with UFH or LMWH and subsequently
with LMWH, for a total therapy duration between
6 weeks and 3 months rather than shorter or
longer treatment duration (Grade 2C). For neonates with CSVT with significant hemorrhage,
we suggest either (1) anticoagulation or (2) supportive care with radiologic monitoring of the
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Recommendations
2.22.1. In children with first VTE (CVAD and
non-CVAD related), we recommend acute anticoagulant therapy with either UFH or LMWH
(Grade 1B). We recommend initial treatment
with UFH or LMWH for at least 5 days (Grade 1B).
For ongoing therapy, we suggest LMWH or
UFH. For patients in whom clinicians will subsequently prescribe VKAs, we recommend
beginning oral therapy as early as day 1 and discontinuing UFH/LMWH on day 6 or later than
day 6 if the INR has not exceeded 2.0 compared
with no therapy (Grade 1B).
2.22.2. We suggest that children with idiopathic
VTE receive anticoagulant therapy for 6 to
12 months compared with no therapy (Grade 2C).
Underlying values and preferences: Families who
place a high value on avoiding the unknown risk of
recurrence in the absence of an ongoing risk factor
and a lower value on avoiding the inconvenience of
therapy or potential impact of therapy on growth and
development and bleeding risk associated with antithrombotic therapy are likely to choose to continue
anticoagulant therapy beyond 6 to 12 months.
2.22.3. In children with secondary VTE (ie, VTE
that has occurred in association with a clinical
risk factor) in whom the risk factor has resolved,
we suggest anticoagulant therapy be administered for 3 months (Grade 2C) as compared
with no further therapy. In children who have
ongoing, but potentially reversible risk factors,
such as active nephrotic syndrome or ongoing
asparaginase therapy, we suggest continuing anticoagulant therapy beyond 3 months in either
therapeutic or prophylactic doses until the risk
factor has resolved (Grade 2C).
2.22.4. In children with recurrent idiopathic
VTE, we recommend indefinite treatment with
VKAs (Grade 1A).
2.22.5. In children with recurrent secondary
VTEs with an existing reversible risk factor for
thrombosis, we suggest anticoagulation until
resolution of the precipitating factor but for a
minimum of 3 months as compared with no further therapy (Grade 2C).
2.22.6. In children with a CVAD in place who
have a VTE, if a CVAD is no longer required, or
is nonfunctioning, we recommend it be removed
(Grade 1B). We suggest at least 3 to 5 days of
anticoagulation therapy prior to its removal
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There are two RCTs reporting thromboprophylaxis of CVADs to prevent CVAD-related DVT.113
The PROTEKT Study randomized 186 children
aged 3 months with varying underlying conditions
to reviparin (n 5 92) (anti-Xa levels, 0.1-0.3 units/mL)
vs standard care (n 5 94) (up to 3 units/kg per h
UFH).113 The incidence of asymptomatic CVADrelated thrombosis was 14.1% (11/78) in the reviparin
group vs 12.5% (10/80) in the standard care group
(OR, 1.15; 95% CI, 0.42-3.23).113 The study was
closed early because of slow patient recruitment.
Schroeder et al47 reported a single-center RCT comparing 10 units/kg per h continuous UFH infusion
to placebo in 90 children aged , 1 year with CVADs
postcardiac surgery. There was no difference in CVADrelated thrombosis in the treatment or placebo groups
(15% vs 16%; difference of 1%; 95% CI, 214%-16%).
The study was closed after an interim analysis showed
futility.
The incidence of CVAD-related thrombosis varies
with the underlying patient population, and this has
led to some more-specific disease-related studies
to examine the role of primary prophylaxis. CVADrelated thrombosis is reported to be common in
children with cancer.484,485 There are two RCTs that
studied thromboprophylaxis in children with cancer.
The Prophylactic Antithrombin Replacement in Kids
with Acute Lymphoblastic Leukemia Treated with
Asparaginase (PARKAA) trial studied the use of antithrombin concentrate vs no therapy in 85 patients
with pediatric acute lymphoblastic leukemia (ALL)
treated with asparaginase.486 Seven of 25 (28%) patients
treated with antithrombin compared with 22 of 60
(37%) not treated had thrombosis (difference, 29%;
95% CI, 230%-13%), but the study was not powered
to show efficacy. Ruud et al529 studied the use of warfarin compared with no therapy in the prevention of
CVAD-related thrombosis in children with cancer.
The study enrolled 73 children, and 15 of 31 (48%)
on warfarin and 17 of 42 (40%) on no therapy developed a VTE (difference, 12%; 95% CI, 215%-31%).
The study was terminated without full recruitment
after an interim study showed futility.
Cohort studies and case series have also addressed
this issue. Elhasid et al107 found LMWH (mean dose,
0.84 mg/kg once daily) to be apparently safe when
compared with historical controls in preventing thrombosis in 41 patients with ALL. Nowak-Gttl et al530
gave LMWH (dose, 1 mg/kg once daily) as primary
thromboprophylaxis to children and adolescents with
Ewing sarcoma (n 5 36) and osteogenic sarcoma
(n 5 39). None of the patients developed TE complications during the postoperative period. Meister et al531
reported that enoxaparin (1 mg/kg per day) in addition to antithrombin supplementation reduced the
rate of thrombosis in children with ALL and CVADs
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Recommendation
2.35. For children who have a BCPS, we suggest
postoperative UFH (Grade 2C).
2.36 Fontan Surgery
Recommendation
2.31. For children with short- or medium-term
CVADs, we recommend against the use of routine systemic thromboprophylaxis (Grade 1B).
The incidence of CVAD-related VTE in children
receiving long-term total parenteral nutrition (TPN)
varies from 1% based on clinical diagnosis to 35%
based on ventilation perfusion scans or echocardiography to 75% based on venography.444,532-538
Two studies have reported the use of VKA primary
prophylaxis in this group of patients.444,535 However,
VKA primary prophylaxis commonly is used for children receiving long-term home parenteral nutrition,
despite the lack of similar practice in adults.
Recommendation
2.34. For children receiving long-term home
TPN, we suggest thromboprophylaxis with VKAs
(Grade 2C).
2.35 Glenn Procedure or Bilateral
Cavopulmonary Shunt
Glenn successfully performed the classic cavopulmonary anastomosis in 1957 as palliation for tricuspid
atresia. The bidirectional Glenn procedure is now
frequently used as an intermediate step in patients
with single ventricles prior to definitive Fontan surgery (following Blalock-Taussig shunts in hypoplastic
right-side hearts and following stage I Norwood procedure in hypoplastic left-side hearts). Thrombotic
complications following the Glenn shunt procedure
are infrequent.539-544 No published data support
the need for routine thromboprophylaxis. However,
once again, the fact that many patients subsequently
proceed to Fontan procedures has led to some suggestions that thromboprophylaxis is warranted after a
Glenn shunt to reduce the risk of thrombosis in the
pulmonary vasculature, hence increasing the likelihood of successful conversion to a full Fontan circuit.
Current clinical practices vary, and include no anticoagulation, UFH followed by aspirin, and UFH followed by warfarin therapy. There is no evidence to
support a preference for any of these approaches.
Recommendations for patients undergoing a bilateral
cavopulmonary shunt (BCPS) procedure are theree772S
fore based on generalization from other major vascular procedures in infants and children.
e773S
e775S
e777S
vasculopathy may be increased compared with idiopathic stroke in children.413,725,739 Sequential imaging
studies may be required to differentiate the diagnosis, and ancillary studies (eg, varicella serology) are
important. Determination of the specific subtype of vasculopathy and monitoring of cerebral vessel appearance on magnetic resonance angiography or formal
angiography are critical for determining ongoing therapy requirements. In cerebral vasculitis, immunosuppressive agents may be required.740
Recommendation
2.55. For children with acute AIS secondary to
non-Moyamoya vasculopathy, we recommend
UFH or LMWH or aspirin for 3 months as initial
therapy compared with no treatment (Grade 1C).
For children with AIS secondary to nonMoyamoya vasculopathy, we suggest that ongoing
antithrombotic therapy should be guided by
repeat cerebrovascular imaging.
2.56-2.57 Moyamoya Disease
The most severe childhood cerebral vasculopathy
is Moyamoya, a progressive bilateral intracranial cerebral arteriopathy with severe stenosis or occlusion
of the terminal internal carotid arteries, typically
accompanied by basal collateral vessels.671 Recurrent
sequential infarcts, some silent, often are present at
diagnosis. The mechanisms for ischemia and infarction likely involved both chronic underperfusion and
thrombotic occlusion. Clinical presentations include
recurrent abrupt AIS and TIA presentations and progressive cognitive loss. Children with vascular stenosis or Moyamoya have a risk of recurrence as high
as 66%.413,725,741 Direct and indirect revascularization procedures to bypass the stenotic and occluded
arteries are available to increase regional cerebral
blood flow and reduce the risk of recurrence,742,743
and a meta-analysis of . 1,000 children confirmed
that surgery confers symptomatic benefit in almost
90% of children.744 A summary of evidence supporting the variety of surgical interventions is available.671
Anticoagulation is less frequently used because of
concerns about bleeding; however, the use of antiplatelet therapy is common. Few data confirm benefit in either the short or long term, although some
studies suggest that medical therapy is important perioperatively to reduce the risk of procedure-associated
strokes, which are common.745
Recommendations
2.56. For children with acute AIS secondary
to Moyamoya, we suggest aspirin over no treatment as initial therapy (Grade 2C).
www.chestpubs.org
e779S
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CHEST
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Retrospective
cohort
Retrospective
cohort
Case series
Case series
RCT
Cohort
Biss et al2/2008
Goldenberg et al3/2005
Massicotte et al5/2003
Streif et al6/2003
Design
Blatn and
Fiamoli1/2009
Study/Year
LMWH (anti-Xa
0.5-1.0 units/mL)
UFH/VKA
(INR 2-3)
46% in TTR
Reviparin
(anti-Xa
0.5-1.0 units/mL)
75% in range
Enoxaparin
(anti-Xa
0.5-1.0 units/mL)
Duration 5-616 d
enoxaparin
Previous
anticoagulation,
lytic therapy,
or both
LMWH (anti-Xa
0.5-1.2 units/mL)
VKA (INR 2-3)
UFH (anti-Xa
0.35-0.7 units/mL)
LMWH (anti-Xa
0.5-1.0 units/mL)
VKA (INR 2.5),
(range, 2-3)
LMWH (anti-Xa
0.5-1.0 units/mL)
Treatment Target
Levels
N 5 62
Reviparin, n 5 36
N 5 78, N 5 76 evaluable
UFH/VKA, n 5 40
N 5 245
Age, 33 d-17.3 y
56% neonates
VTE, 84%
Arterial TE, 5%
N 5 11
LMWH, n 5 4
VKA, n 5 1
Lemierre
syndrome, n 5 6
Pulmonary embolus,
N 5 56
UFH, n 5 36
Thrombolysis, n 5 8
IVC filter, n 5 7
Thrombectomy, n 5 2
N 5 33
IV LMWH, n 5 21
Subcutaneous
LMWH, n 5 12
No. Patients
1.2/100 treatment-y
3 mo therapy
plus 3 mo
follow-up
Mean, 3 d-6.6 y
(median, 6 m);
190 had
evaluable
ultrasounds
Median, 1 y (range,
7 wk-12 mo)
Median, 56 mo
Range 5-93 mo
Not stated
Follow-up
n54
2 (5.6%)
2 (5.6%)
n53
5 (12.5%)
No reported
events
No reported
events
n 5 12
Fatal bleeding
n52
Major
Hemorrhage
4 (10%)
Developed PE,
n55
No reported
events
Early progression,
n 54
Recurrence, n 5 7
Fatal thrombosis,
n 55
Thromboembolic
Events
Table S1[Recommendation 2.22.1] Evidence Profile: Studies Assessing Anticoagulation for VTE in Children
(Continued)
Underpowered
At follow-up 4-6 mo
postdiagnosis
n 5 2 persistent
thrombosis
n 5 4 recanalized
Full or partial
recanalization:
85% for IV LMWH,
66% for
subcutaneous
LMWH
Comments
2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American
College of Chest Physicians
(www.chestjournal.org/site/misc/reprints.xhtml).
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from chestjournal.chestpubs.org atDOI:
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on February 22, 2012
Retrospective
case series
Case series
Case series
Case series
Dix et al8/2000
Punzalan et al9/2000
Nohe et al10/1999
Design
Hofmann et al7/2001
Study/Year
N5 19
Prospective, n 5 6
Retrospective, n 5 13
VTE, n 5 14
Primary prophylaxis,
n55
N 5 48
VTE, n 5 19
Dalteparin 129
43 units/kg per d
(anti-Xa 0.4-1.0 units/mL)
n 5 66
n 5 13
48 girls
31 boys
Aged 2 wk-19 y,
Mean, 11.8 y
No. Patients
Enoxaparin
(anti-Xa 0.5-1.2 units/mL)
Enoxaparin or lytic
therapy
Enoxaparin (anti-Xa
0.5-1.0 units/mL)
Low-risk prophylaxis (anti-Xa
0.1-0.4 units/mL) VKA
added in 47 of 146
Nadroparin
Enoxaparin (anti-Xa
0.5-1.0 units/mL)
Treatment Target
Levels
Not reported
Not reported
Duration of therapy:
n 5 74 of
146 20 d
treatment
Not reported
N 5 62 short-term
prophylaxis
(1-2 wk)
N 5 13 (long-term
therapy and
follow-up)
Follow-up
Table S1Continued
None reported
No new/recurrent
VTE
n 5 2 (1.3%)
recurrent/new
VTE when patient
subtherapeutic
n51
Thromboembolic
Events
None reported
No major
hemorrhage
n 5 7 (5%) major
n50
Major
Hemorrhage
(Continued)
n 5 6 complete
recanalization
n 5 5 partial
recanalization
n 5 7 no recanalization
Unable to determine
which patients were
treated for VTE
vs primary
prophylaxis
n 5 12 lost to
follow-up;
transferred to other
hospitals and two
deaths directly related
to therapy (one
hemorrhage; one TE)
n 5 4 no reocclusion
n 5 2 recanalized
n 5 1 reocclusion
Unable to separate
which patients
received enoxaparin
vs nadroparin
Comments
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Case series
Prospective
cohort
Prospective
cohort
Massicotte et al12/1996
Andrew et al13/1994
Andrew et al14/1994
VKA
1. INR 2-3 3 3-6 mo
followed by
INR 1.3-1.8 secondary
prophylaxis
2. 1.3-1.8 primary
prophylaxis
3. 2.5-3.5
(mechanical valves)
Enoxaparin (anti-Xa
0.5-1.0 units/mL)
VKA
n 5 52, (INR 1.4-1.8)
n 5 263, (INR 2-3)
n 5 (INR 2.5-3.5)
n 5 208 primary
prophylaxis
n 5 144 secondary
prophylaxis
49-61% TTR
Treatment Target
Levels
N 5 115
Secondary prophylaxis,
n 5 54
Primary prophylaxis,
n 5 61
N 5 65
Follow-up, N 5 65
n 5 29, , 1 y
n 5 36, 1-18 y
VTE, n 5 30
(n 5 9 , 1 y)
Arterial thrombosis,
n 5 11
N 5 25
VTE, n 5 14
CNS, n 5 9
CHD prophylaxis,
n52
N 5 319
352 courses of
therapy
391 treatment-y
Age, 1 mo-18 y
No. Patients
Duration of therapy
n 5 37, 3-6 mo
n 5 38, 6 mo
n 5 40,
lifelong
18 mo
Not reported
Variable duration
of therapy
Range, 10-50 d
Median, 6 mo
Follow-up
n 5 4 new/recurrent
thrombosis after
VKA therapy
discontinued
n52
No new/recurrent
VTE
n58
n 5 6, after VKA
therapy
discontinued
n52
1.3% per patient-y,
during VKA
therapy
Thromboembolic
Events
n52
n51
n52
n52
0.5%/patient-y
Major
Hemorrhage
Comments
CHD 5 congenital heart disease; INR 5 international normalized ratio; LMWH 5 low-molecular-weight heparin; PTT 5 partial thromboplastin time; TE 5 thromboembolism; TTR 5 time in therapeutic
range; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist.
11
Prospective
cohort
Design
Streif et al /1999
Study/Year
Table S1Continued
References
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2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American
College of Chest Physicians
(www.chestjournal.org/site/misc/reprints.xhtml).
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